This proposal is for a multi-disciplinary stroke program that will focus on defining processes that appear to be of critical importance in the initiation of ischemic stroke. The aim of the program is to delineate the relationship between stroke, stroke risk factors, and hemostasis regulation of the brain and will utilize clinical, animal, and cell culture studies. Project 1 is a case-control study, the purpose of which is to define the relationship between ischemic stroke, stroke risk factors, infectious and inflammatory processes, and hemostasis function. Project 2 studies the interaction of stroke risk factors, endotoxin exposure, and extracranial artery occlusion on brain hemostasis regulation in the rat model. Project 3 investigates brain capillary hemostasis at a cellular and molecular level by studies of CNS-derived human brain endothelium; the emphasis is on the effects of plasma factors associated with stroke risk factors and the impact of inflammatory cytokines on CNS- derived endothelial hemostasis function. The projects are linked by a common focus of interests, and studies performed by the laboratories of each project that directly assist with the specific aims of other projects. Completion of this program will substantially enhance our knowledge of processes relevant to ischemic stroke pathogenesis leading to new strategies for stroke prevention.